2-Octulosonic acid inhibitors

The research team of J. Tadanier prepared a series of C8-modified 3-deoxy-P-D-manno-2-octulosonic acid analogues as potential inhibitors of CMP-Kdo synthetase. One of the derivatives was prepared from a functionalized olefinic carbohydrate substrate by means of the Wohl-Ziegler bromination. The stereochemistry of the double bond was (Z), however, under the reaction conditions a cis-trans isomerization took place in addition to the bromination at the allylic position (no yield was reported for this step). It is worth noting that the authors did not use a radical initiator for this transformation, the reaction mixture was simply irradiated with a 150W flood lamp. Subsequently the allylic bromide was converted to an allylic azide, which was then subjected to the Staudinger reaction to obtain the corresponding allylic amine. 

Tadanier, J., Lee, C. M., Whittern, D., Wideburg, N. Synthesis of some C-8-modified 3-deoxy-]3-D-manno-2-octulosonic acid analogs as inhibitors of CMP-Kdo synthetase. Carbohydr. Res. 1990, 201, 185-207. 

Waglund, T., Luthman, K., and Orbe, M., Synthesis of C-(P-D-glycosyl) analogues of 3-deoxy-D-manno-2-octulosonic acid (Kdo) as potential inhibitors of CMP-Kdo synthetase, Carbohydr. Res., 206, 269, 1990. 

Other Aldolases. In addition to the DHAP aldolases, we have conducted preliminary investigations of two other aldolases. KDO synthase (E.C. 4.1.2.16) catalyzes the formation of 2-keto-3-deoxy-L-nrahi/io-octulosonic acid 8-phosphate (KDO-8-P) from arabinose 5-phosphate and PEP (Scheme 10) (29). KDO is an integral component of Gram-negative bacterial cell walls, and derivatives of KDO are of interest as inhibitors of cell wall formation (30, 31). 

Deoxv-6-thio-D-manno-2-octulosonic acid (6-thio-KDO), a potential inhibitor of CHP-KDO synthetase, has been prepared. Its ammonium salt failed however to inhibit this enzyme. 3-Deoxy-5-thiopentopyranoses with branch-points at C-3 have been synthesized from non-carbohydrate precursors (3) (see Vol 20, p 148 for their preparation) as shown in Scheme 1. The Pummerer rearrangement of... 

The a- and P-glycopyranosyl phosphates of 3-deoxy-D-ma no-2-octulosonic acid have been prepared from Kdo as inhibitors of 3-deoxy-D-/nowio-2-octuloso-nate-8-phosphate synthase, which occurs in Gram-negative bacteria. iV-Acetyl-neuraminic add has been 0-alkylated at C-4 by selective alkylation of an 8,9-0-isopropylidene derivative, and treatment of the a-benzyl glycoside of N-acetylneuraminic acid with iluoroacetyl imidazole has afforded a mixture of 4,5-and 4,9-di-0-(fluoroacetyl) derivatives. A 4-acetamido-4-deoxy-4-epi-derivative of -acetylneuraminic acid has been prepared using standard techniques. ... 

CMP-KDO synthetase (cytidine-5 -triphosphate cytidine-5 -mon-ophosphate-3-deoxy-D-manno-octulosonate cytidylyltransferase), the next enzyme in the pathway, catalyzes the formation of the nucleotide sugar, CMP-KDO from CTP and KDO. This enzyme was first studied by Ghalambor and Heath (IT). We have purified this enzyme to homogeneity (27). T i apparent K values for CTP nd KDO in the presence of 10 mM Mg were determined to be 2 x 10 M and 2.9 x 10 M, respectively. The enzy tic reaction was dependent upon the addition of CTP, KDO and Mg but did not require a reducing agent. The formation of CMP-KDO was not inhibited by the addition of CDP, CMP, KDO-8-phosphate or N-acetylneuraminic acid to the complete reaction mixture. In agreement with Ghalambor and Health (17), neither KDO-8-phosphate nor N-acetylneuraminic acid could substitute for KDO in the reaction mixture. Pyrophosphate, one of the end products, is a weak inhibitor of the reaction with an apparent Ijq value of 5.0 mM. The addition of CMP,CD or any of the other mono- or di-nucleotides did not inhibit the reaction. 

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